US5227399AExpiredUtilityPatentIndex 60
Pyranylphenyl naphthalene lactones as inhibitors of leukotriene biosynthesis
Est. expiryFeb 28, 2011(expired)· nominal 20-yr term from priority
Inventors:YOUNG ROBERT NGIRARD YVESGILLARD JOHN WTRIMBLE LAIRD ASCHEIGETZ JOHNYERGEY JAMES ADUCHARME YVESNICOLL-GRIFFITH DEBORAH AHUTCHINSON JOHN H
C07D 307/92C07D 409/12C07D 493/08C07D 407/12
60
PatentIndex Score
3
Cited by
13
References
10
Claims
Abstract
Compounds having the formula I: ##STR1## are inhibitors of leukotriene biosynthesis. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis and allograft rejection and in preventing the formation of atherosclerotic plaques.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A compound of the formula: ##STR27## wherein: R 1 and R 5 are independently H, OH, lower alkyl, or lower alkoxy; R 2 is H, lower alkyl or together with R 1 forms a double bonded oxygen (═0); R 3 is H, lower alkyl, or together with R 1 forms a carbon bridge of 2 or 3 carbon atoms, said bridge optionally containing a double bond; each R 4 , R 6 and R 7 is independently H or lower alkyl; R 8 is halogen, lower alkyl, or lower alkoxy; each R 9 is independently H, halogen, lower alkyl, or lower alkoxy; R 10 is H, halogen, lower alkyl, or lower alkoxy; X 1 is O, S, S(O), S(O) 2 or CH 2 ; X 2 is C(OR 7 ) or C(R 7 ); X 3 is CH 2 O, OCH 2 , or CH 2 CH 2 ; ○ is phenyl or 1- or 2-naphthyl; m is 0, 1 or 2; n is 1; or the pharmaceutically acceptable salts thereof.
2. A compound of claim 1 of the formula: ##STR28## wherein the substituents are: __________________________________________________________________________
EX.
R.sup.1
R.sup.3
R.sup.5
R.sup.8
X.sup.1
X.sup.2
X.sup.3
__________________________________________________________________________
1 H H H H O C(OMe)
CH.sub.2 O
2 H H H H O C(OMe)
OCH.sub.2
3 H H H 4-F O C(OMe)
CH.sub.2 O
4 H H H H O C(OH)
CH.sub.2 O
5 H H H H O C(OEt)
CH.sub.2 O
6 H H H H CH.sub.2
C(OMe)
CH.sub.2 O
9 H H OH H O C(OMe)
CH.sub.2 O
10 OH H H H O C(OMe)
CH.sub.2 O
11 OH H H H O C(OH)
CH.sub.2 O
12 H H OH H O C(OH)
CH.sub.2 O
13 OH H OH H O C(OH)
CH.sub.2 O
14 H H Me H O C(OMe)
CH.sub.2 O
15 OH H OH H O C(OMe)
CH.sub.2 O
16*
Me Me H H O C(OH)
CH.sub.2 O
17*
Me Me H H O C(OH)
CH.sub.2 O
18 H H H 4-Cl
O C(OH)
CH.sub.2 O
19 H H H 4-OMe
O C(OH)
CH.sub.2 O
20 Me Me H H O C(OMe)
CH.sub.2 O
21 H H H H S C(OH)
CH.sub.2 O
22 H H H H S(O)
C(OH)
CH.sub.2 O
23 H H H H S(O).sub.2
C(OH)
CH.sub.2 O
24**
OMe H H H O C(OH)
CH.sub.2 O
25**
OMe H H H O C(OH)
CH.sub.2 O
26 H H H H O C(Me)
CH.sub.2 O
27 H H Me H O C(OH)
CH.sub.2 O
28 H H H 4-F O C(OH)
CH.sub.2 O
29 H H H H O C(Et)
CH.sub.2 O
30 H H H 2-F O C(OH)
CH.sub.2 O
31 H H H 2-Cl
O C(OH)
CH.sub.2 O
32 H H H 3-OMe
O C(OH)
CH.sub.2 O
33**
OCH(Me).sub.2
H H H O C(OH)
CH.sub.2 O
34**
OCH(Me).sub.2
H H H O C(OH)
CH.sub.2 O
35 (R.sup.1 R.sup.3) =
--CH═CH--
H H O C(OH)
CH.sub.2 O
36 (R.sup.1 R.sup.3) =
--CH.sub.2 CH.sub.2 --
H H O C(OH)
CH.sub.2 O
__________________________________________________________________________
*cis and trans isomers
**axial and equatorial isomers
3. A compound of claim 1 of the formula: ##STR29## wherein the substituents are: ______________________________________
EX. R.sup.1 R.sup.2
R.sup.3
R.sup.4
R.sup.5
R.sup.6
R.sup.9
R.sup.10
X.sup.1
______________________________________
37 H H H H H H H 4- O
OMe
38 H H H H Me Me H H O
39 H H H H H H 1- H O
OMe
40 Me Me Me Me H H H H S
41 (R.sup.1
═O H H H H H H O
R.sup.2) =
______________________________________
4. The following compounds of claim 1: 3-Hydroxymethyl-4-phenyl-7-{3-[4-[(4-methoxy)tetrahydropyranyl]benzyloxy}-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-phenyl-7-{3-[4-(4-methoxy)tetrahydropyranyl]phenoxymethyl}-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-(4-fluorophenyl)-7-{3-[4-(4-methoxy)tetrahydropyranyl]benzyloxy}-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-phenyl-7-{3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy}-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-phenyl-7-{3-[4-(4-ethoxy)tetrahydropyranyl]benzyloxy}-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-phenyl-7-{3-(1-methoxycyclohexyl)benzyloxy}-2-naphthoic acid, lactone form; 3-Formyl-4-phenyl-7-{3-[4-(4-methoxy)tetrahydropyranyl)benzyloxy}-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-phenyl-7-[3-[4-(2,4-dihydroxy)tetrahydropyranyl]benzyloxy]-2-naphthoic acid, lactone form; 3-Formyl-4-phenyl-7-[3-[4-(4-hydroxy)tetrahydropyranyl[benzyloxy]-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-phenyl-7-[3-[4-(4α-hydroxy-2,6-dimethyl)tetrahydropyranyl]benzyloxy]-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-phenyl-7-[3-[4-(4β-hydroxy-2,6-dimethyl)tetrahydropyranyl]benzyloxy]-2-naphthoic acid lactone form; 3-Hydroxymethyl-4-(4-chlorophenyl)-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-(4-methoxyphenyl)-7-[3-[4-hydroxy)tetrahydropyranyl]benzyloxy]-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-phenyl-7-[3-[4-(4α-methoxy-2,6-dimethyl)tetrahydropyranyl]benzyloxy]-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy)tetrahydrothiopyranyl]benzyloxy]-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-S-oxo)tetrahydrothiopyranyl]benzyloxy]-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-S,S-dioxo)tetrahydrothiopyranyl]benzyloxy]-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-2α-methoxy)tetrahydropyranyl]benzyloxy]-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-2β-methoxy)tetrahydropyranyl]benzyloxy]-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-methyl)tetrahydropyranyl]benzyloxy]-2-naphthoic acid, lactone form; 3-(1-Hydroxyethyl)-[3-[4-hydroxy)tetrahydropyranyl]benzyloxy]-4-phenyl-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-(4-fluorophenyl)-7-[3-[4-(4-hydroxy)-tetrahydropyranyl]benzyloxy]-2-naphthoic acid lactone form; 3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-ethyl)tetrahydropyranyl]benzyloxy]-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-(fluorophenyl)-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-(2-chlorophenyl)-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-2-naphthoic acid lactone form; 3-Hydroxymethyl-4-(3-methoxyphenyl)-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-2α-isopropyloxy)tetrahydropyranyl]benzyloxy]-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-2β-isopropyloxy)tetrahydropyranyl]benzyloxy]-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-phenyl-7-[3-[3-(8-oxabicyclo[3.2.1]oct-6-en-3α-ol)]benzyloxy]-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-phenyl-7-[3-[3-(8-oxabicyclo[3.2.1]octan-3α-ol)]benzyloxy]-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-phenyl-7-[3-[4-(hydroxy)tetrahydropyranyl]-4-methoxybenzyloxy]-2-naphthoic acid, lactone form; 3-(1-Hydroxy-1-methylethyl)-4-phenyl-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-1-naphthoic acid, lactone form; 3-Hydroxymethyl-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-1-methoxy-4-phenyl-2-naphthoic acid, lactone form; 3-Hydroxymethyl-4-phenyl-7-[3-[4-(4α-hydroxy-2,2,6,6-tetramethyl)tetrahydrothiopyranyl]benzyloxy]-2-naphthoic acid, lactone form; or 3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-2-oxo)tetrahydropyranyl]benzyloxy-2-naphthoic acid, lactone form.
5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
6. A method of preventing the synthesis, the action, or the release of SRS-A or leukotrienes in a mammal which comprises administering to said mammal an effective amount of a compound of claim 1.
7. The method of claim 6 wherein the mammal is man.
8. A method of treating asthma in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1.
9. A method of treating inflammatory diseases of the eye in a mammal which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1.
10. The method of claim 9 wherein the mammal is man.Cited by (0)
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